Alternative titles; symbols
HGNC Approved Gene Symbol: TAF8
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38) : 6:42,050,524-42,087,462 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.1 | Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy | 619972 | Autosomal recessive | 3 |
Human transcription factor IID (TFIID; 313650) is a general initiation factor that contains TATA-binding protein (TBP; 600075) and several TBP-associated factors (TAFs), including TAF8 (TBN). TFIID, through core promoter recognition, nucleates the assembly of other general initiation factors and RNA polymerase II (see 180660) into a functional preinitiation complex, and it is required for basal and activator-dependent transcription (Guermah et al., 2003).
By screening a HeLa cell cDNA library using degenerate primers based on peptide sequences derived from purified TAF8, Guermah et al. (2003) cloned TAF8. The deduced 310-amino acid protein contains an N-terminal H4 (see 602822)-like histone fold and shares 95.5% amino acid identity with mouse Tbn, a protein essential for early development.
By coimmunoprecipitation analysis of HeLa cell TFIID complexes, Guermah et al. (2003) found that TAF8 was a component of at least a subpopulation of TFIID complexes that supported both basal and activated transcription. By incubation with individual recombinant proteins prior to immunoprecipitation, Guermah et al. (2003) showed that TAF8 bound substantial amounts of TBP, TAF6 (602955), and TAF11 (600772), as well as lower amounts of TAF1 (313650) and TAF12 (600773), but not other TAFs tested. TAF8 interacted strongly with TAF10 (600475), and the interaction required the histone fold, but not the C-terminal portion, of TAF8. Taf8 was induced and sequestered within TFIID upon differentiation of mouse preadipocytes to adipocytes, whereas expression of all other TAFs tested was slightly reduced. When ectopically expressed, the histone fold domain of TAF8 acted as a dominant-negative mutant and selectively inhibited adipogenic differentiation. Overexpressed TAF8 acted as a positive adipogenesis regulator and reversed the inhibitory effect of the histone fold domain.
Cryoelectron Microscopy
Bieniossek et al. (2013) presented the structure of the human core-TFIID complex, consisting of 2 copies each of TAF4 (601796), TAF5 (601787), TAF6, TAF9 (600822), and TAF12, determined by cryoelectron microscopy at 11.6-angstrom resolution. The structure revealed a 2-fold symmetric, interlaced architecture, with pronounced protrusions, that accommodates all conserved structural features of the TAFs including the histone folds. Bieniossek et al. (2013) further demonstrated that binding of 1 TAF8-TAF10 complex breaks the original symmetry of the core-TFIID. Bieniossek et al. (2013) proposed that the resulting asymmetric structure serves as a functional scaffold to nucleate holo-TFIID assembly, by accreting 1 copy each of the remaining TAFs and TBP.
Stumpf (2022) mapped the TAF8 gene to chromosome 6p21.1 based on an alignment of the TAF8 sequence (GenBank AK303097) with the genomic sequence (GRCh38).
In a 4.5-year-old girl, born of unrelated Hispanic parents, with neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy (NEDMLHB; 619972), El-Saafin et al. (2018) identified a homozygous splice site mutation in the TAF8 gene (c.781-1G-A; 609514.0001). The mutation, which was found by exome sequencing, was inherited from each unaffected parent who was heterozygous for the mutation.
In 5 patients (patients 3-7) from 3 unrelated consanguineous families with NEDMLHB, Wong et al. (2022) identified a homozygous c.781-1G-A transition in the TAF8 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. Functional studies of this variant were not performed. In addition, 2 German sisters (patients 1 and 2) with the disorder were found to be compound heterozygous for 2 splice site mutations in the TAF8 gene (609514.0002 and 609514.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of patient fibroblasts showed aberrant transcripts related to 1 of the mutations, a 70% reduction of TAF8 mRNA transcripts, and a significant reduction in TAF8 protein compared to controls. TAF8 immunoreactivity was decreased in patient fibroblasts, particularly in the nucleus.
In a 4.5-year-old girl, born of unrelated Hispanic parents, with neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy (NEDMLHB; 619972), El-Saafin et al. (2018) identified a homozygous G-to-A transition in intron 7 of the TAF8 gene (c.781-1G-A, NM_138572.2). The mutation, which was found by exome sequencing, was inherited from each unaffected parent who was heterozygous for the mutation. The variant was found in the heterozygous state in 10 individuals in the gnomAD database, including 5 of Hispanic origin (10 of 277,264 alleles). Analysis of patient cells showed that the variant caused a splicing defect, a frameshift, and premature termination, and that the mutant transcript was subject to nonsense-mediated mRNA decay. However, mutant TAF8 mRNA was only mildly reduced by about 30% compared to controls. The predicted truncated protein would lack the C-terminal nuclear localization signal, but Western blot analysis did not detect a mutant protein, suggesting that it is unstable and prone to degradation, most likely by the proteasome. These findings suggested a loss-of-function effect. El-Saafin et al. (2018) noted that knockdown of the Taf8 gene in mice causes blastocyst death in early development at around embryonic day 4 due to apoptosis of the inner cell mass. In vitro functional cellular expression studies confirmed that deletion of Taf8 in mouse embryonic stem cells resulted in increased cell death that was associated with transcriptional defects. Patient fibroblasts showed evidence of impaired assembly of the TFIID complex. However, patient fibroblasts demonstrated normal recruitment of RNA polymerase II to active promoters and transcription rates that were similar to those of controls. El-Saafin et al. (2018) speculated that the mutation did not cause a complete loss of function since the patient survived embryonic development.
In 5 patients (patients 3-7) from 3 unrelated consanguineous families with NEDMLHB, Wong et al. (2022) identified a homozygous c.781-1G-A transition ion the TAF8 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. Functional studies of this variant were not performed.
In 2 German sisters (family A) with neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy (NEDMLHB; 619972), Wong et al. (2022) identified compound heterozygous splice site mutations in the TAF8 gene: an A-to-G transition in intron 1 (c.45+4A-G, NM_138572.2) and a c.489G-A transition (609514.0003) that affected the donor site of exon 5. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The c.45+4A-G mutation was not present in the gnomAD database, whereas c.489G-A was present at a low frequency. Analysis of patient fibroblasts showed 2 novel splice site variants that caused frameshifts involving exons 5 and 6, predicted to result in premature termination (Pro122LeufsTer98 and Pro122HisfsTer4). These aberrant products were likely due to the c.489G-A variant. The largest transcript identified showed a wildtype sequence, suggesting that the c.45+4A-G mutation may be leaky, leading to production of a normal transcript and possibly an unstable small mutant transcript that is undetectable. Further analysis demonstrated a 70% reduction of TAF8 mRNA transcripts and a significant reduction in TAF8 protein compared to controls. TAF8 immunoreactivity was decreased in patient fibroblasts, particularly in the nucleus.
For discussion of the c.489G-A transition (c.489G-A, NM_138572.2) affecting the exon 5 donor splice site of the TAF8 gene that was found in compound heterozygous state in 2 sibs with neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy (NEDMLHB; 619972) by Wong et al. (2022), see 609514.0002.
Bieniossek, C., Papai, G., Schaffitzel, C., Garzoni, F., Chaillet, M., Scheer, E., Papadopoulos, P., Tora, L., Schultz, P., Berger, I. The architecture of human general transcription factor TFIID core complex. Nature 493: 699-702, 2013. [PubMed: 23292512] [Full Text: https://doi.org/10.1038/nature11791]
El-Saafin, F., Curry, C., Ye, T., Garnier, J.-M., Kolb-Cheynel, I., Stierle, M., Downer, N. L., Dixon, M. P., Negroni, L., Berger, I., Thomas, T., Voss, A. K., Dobyns, W., Devys, D., Tora, L. Homozygous TAF8 mutation in a patient with intellectual disability results in undetectable TAF8 protein, but preserved RNA polymerase II transcription. Hum. Molec. Genet. 27: 2171-2186, 2018. [PubMed: 29648665] [Full Text: https://doi.org/10.1093/hmg/ddy126]
Guermah, M., Ge, K., Chiang, C.-M., Roeder, R. G. The TBN protein, which is essential for early embryonic mouse development, is an inducible TAFII implicated in adipogenesis. Molec. Cell 12: 991-1001, 2003. [PubMed: 14580349] [Full Text: https://doi.org/10.1016/s1097-2765(03)00396-4]
Stumpf, A. M. Personal Communication. Baltimore, Md. 07/28/2022.
Wong, K. M., Jepsen, W. M., Efthymiou, S., Salpietro, V., Sanchez-Castillo, M., Yip, J., Kriouile, Y., Diegmann, S., Dreha-Kulaczewski, S., Altmuller, J., Thiele, H., Nurnberg, P., and 9 others. Mutations in TAF8 cause a neurodegenerative disorder. Brain 145: 3022-3034, 2022. [PubMed: 35759269] [Full Text: https://doi.org/10.1093/brain/awac154]